Identification and characterization of somatic mutations in cancer have important prognostication and treatment implications. Genes encoding the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor and its negative regulator, Kelch-like ECH-associated protein 1 (KEAP1), are frequently mutated in cancer. These mutations drive constitutive NRF2 activation and correlate with poor prognosis. Despite its apparent significance, a comprehensive catalogue of somatic NRF2 mutations across different tumor types is still lacking. Here, we catalogue NRF2 mutations in The Cancer Genome Atlas (TCGA) database. 226 unique NRF2-mutant tumors were identified from 10,364 cases. NRF2 mutations were found in 21 out of the 33 tumor types. A total of 11 hotspots were identified. Of these, mutation to the R34 position was most frequent. Notably, R34 and D29 mutations were overrepresented in bladder, lung, and uterine cancers. Analyses of corresponding RNA sequencing data using a de novo derived gene expression classifier showed that the R34 mutations drive constitutive NRF2 activation with a selection pressure biased against the formation of R34L. Of all R34 mutants, R34L conferred the least degree of protein stabilization, suggesting a pro-tumor NRF2 half-life threshold. Our findings offer a comprehensive catalogue of NRF2 mutations in cancer that can help prognostication and NRF2 research.

Quantitative data on human-environment interactions are needed to fully understand infectious disease transmission processes and conduct accurate risk assessments. Interaction events occur during an individual's movement through, and contact with, the environment, and can be quantified using diverse methodologies. Methods that utilize videography, coupled with specialized software, can provide a permanent record of events, collect detailed interactions in high resolution, be reviewed for accuracy, capture events difficult to observe in real-time, and gather multiple concurrent phenomena. In the accompanying video, the use of specialized software to capture human-environment interactions for human exposure and disease transmission is highlighted. Use of videography, combined with specialized software, allows for the collection of accurate quantitative representations of human-environment interactions in high resolution. Two specialized programs include the Virtual Timing Device for the Personal Computer, which collects sequential microlevel activity time series of contact events and interactions, and LiveTrak, which is optimized to facilitate annotation of events in real-time. Opportunities to annotate behaviors at high resolution using these tools are promising, permitting detailed records that can be summarized to gain information on infectious disease transmission and incorporated into more complex models of human exposure and risk.

Scholarly disciplines are ever-changing and continuously debated constellations of intellectual heritage and contemporary issues. This article discusses debates over anthropological nomenclature, anthropometric indices, and museum exhibit design in the development of European and American anthropology from its ethnological beginnings in the 1840s through nineteenth-century evolutionism to the establishment of the Boasian historical particularist approach after 1904. It also outlines the impacts of those debates and disagreements on the subsequent development of the "four-field approach" in American-university-based anthropology programs. The transitions from ethnology to evolutionism to particularism can be followed through arguments over nomenclature, anthropometrics, and the content and design of museum exhibits, as nascent anthropologists defined and redefined their subfield(s) of study and attempted to become part of the burgeoning Science Establishment of the nineteenth and early twentieth centuries in Europe and North America. The arguments and their (sometimes) resolutions laid the foundations for twentieth-century university-based anthropology programs and ethnographic and archaeological exhibits in anthropology and natural history museums. The article is, thus, a contribution to the developmental history of anthropology in Europe and North America.

The effects of silicon (Si) and salicylic acid (SA) applications on proline content and expression of (1)-pyrrolin-5-carboxylate synthetase (P5CS) were examined under different drought levels and different drought exposure times. Two wheat cultivars, a drought tolerant and a drought sensitive were used. The experiment was a factorial based on completely randomized design with three replicates. Expression analysis by the quantitative real time PCR showed that the tolerant cultivar had significantly higher P5CS expressions compared to the sensitive one under drought stress. In sampling time points, the maximum level of mRNA was observed at 48h after stress was applied. At 48h after stress induction, the expression of P5CS was almost 3.1 fold higher in the tolerant cultivar compared to the sensitive one. In both cultivars, gene expression decreased from 48 to 72h. The stressed plants treated with Si+SA showed a higher expression. Proline content started to increase by Si and SA treatments and the maximum proline content was obtained at simultaneous application of Si+SA. Drought stress significantly reduced chlorophyll content, relative water content and leaf water potential of both cultivars, while increased electrolyte leakage (EL) of the leaves. In contrast, foliar-applied Si and SA significantly increased these parameters and reduced EL, and the effect of simultaneous application of Si and SA was greater. The results suggest that the P5CS is a stress inducible gene. This gene has the potential to be used for improvement of drought stress tolerance in wheat. Network analysis highlighted positive interaction of osmotic stress, drought and cold stress on P5CS1 and the regulatory role of MYB2, ERF-1, and EIN3 transcription factors. In conclusion, alleviation of drought stress by application of Si and SA was associated partially with enhanced expression of P5CS gene and following proline accumulation.

Objectives: To compare pharmacy students' confidence in understanding course material before and after listening to course podcasts; (2) determine whether course content affects pharmacy students' perceptions on podcasts' usefulness; and (3) evaluate English First Language vs. English Second Language speakers' attitudes on podcasts. Methods: First and second year pharmacy students (n=314) who attended a Clinical or Research Methods course in 2012 and 2013 completed pre-and post-test surveys to assess study objectives. Results: Students had more confidence understanding course topics after listening to the podcasts (p<0.05). Significant differences were observed in clinical vs. non-clinical courses. The majority of students across courses agreed or strongly agreed that podcasts were a useful learning tool (91.2% and 92.3% Research and Clinical course, respectively) and promoted understanding of course material (89.3% and 93.9%). There were no statistically significant differences in perceptions among English First Language and English Second Language speakers (p>0.05). Conclusion: Podcasts are beneficial to a majority of pharmacy students, despite language barriers.

Introduction: Treatment-resistant depression, post-traumatic stress disorder, chronic pain, and L-DOPA-induced dyskinesia in Parkinson's disease are characterized by hypersynchronous neural oscillations. Sub-anesthetic ketamine is effective at treating these conditions, and this may relate to ketamine's capacity to reorganize oscillatory activity throughout the brain. For example, a single ketamine injection increases gamma (similar to 40 Hz) and high-frequency oscillations (HFOs, 120-160 Hz) in the cortex, hippocampus, and striatum. While the effects of single injections have been investigated, clinical ketamine treatments can involve 5-h up to 3-day sub-anesthetic infusions. Little is known about the effects of such prolonged exposure on neural synchrony. We hypothesized that hours-long exposure entrains circuits that generate HFOs so that HFOs become sustained after ketamine's direct effects on receptors subside. Methods: Local-field recordings were acquired from motor cortex (M1), striatum, and hippocampus of behaving rats (n = 8), and neural responses were measured while rats received 5 ketamine injections (20 mg/kg, i.p., every 2 h, 10-h exposure). In a second experiment, the same animals received injections of D1-receptor antagonist (SCH-23390, 1 mg/kg, i.p.) prior to ketamine injection to determine if D1 receptors were involved in producing HFOs. Results: Although HFOs remained stable throughout extended ketamine exposure, broad-band high-frequency activity (40-140 Hz) in the hippocampus and delta-HFO cross-frequency coupling (CFC) in dorsal striatum increased with the duration of exposure. Furthermore, while ketamine-triggered HFOs were not affected by D1 receptor blockade, ketamine-associated gamma in motor cortex was suppressed, suggesting involvement of D1 receptors in ketamine-mediated gamma activity in motor cortex. Conclusion: Prolonged ketamine exposure does not enhance HFOs in corticostriatal circuits, but, instead, enhances coordination between low and high frequencies in the striatum and reduces synchrony in the hippocampus. Increased striatal CFC may facilitate spike-timing dependent plasticity, resulting in lasting changes in motor activity. In contrast, the observed wide-band high-frequency "noise" in the hippocampus suggests that ketamine disrupts action-potential timing and reorganizes connectivity in this region. Differential restructuring of corticostriatal and limbic circuits may contribute to ketamine's clinical benefits.

We investigate the properties of galaxies as they shut off star formation over the 4 billion years surrounding peak cosmic star formation. To do this, we categorize similar to 7000 galaxies from 1 < z < 4 into 90 groups based on the shape of their spectral energy distributions (SEDs) and build composite SEDs with R similar to 50 resolution. These composite SEDs show a variety of spectral shapes and also show trends in parameters such as color, mass, star formation rate, and emission-line equivalent width. Using emission-line equivalent widths and strength of the 4000 angstrom break, D(4000), we categorize the composite SEDs into five classes: extreme emission line, star-forming, transitioning, post-starburst, and quiescent galaxies. The transitioning population of galaxies shows modest H alpha emission (EWREST similar to 40 angstrom) compared to more typical star-forming composite SEDs at log(10)(M/M-circle dot) similar to 10.5 (EWREST similar to 80 A). Together with their smaller sizes (3 kpc vs. 4 kpc) and higher Sersic indices (2.7 vs. 1.5), this indicates that morphological changes initiate before the cessation of star formation. The transitional group shows a strong increase of over 1 dex in number density from z similar to 3 to z similar to 1, similar to the growth in the quiescent population, while post-starburst galaxies become rarer at z less than or similar to 1.5. We calculate average quenching timescales of 1.6 Gyr at z similar to 1.5 and 0.9 Gyr at z similar to 2.5 and conclude that a fast-quenching mechanism producing post-starbursts dominated the quenching of galaxies at early times, while a slower process has become more common since z similar to 2.

The epididymis exhibits a less restrictive physical blood-tissue barrier than the testis and, while numerous immunosuppressive factors have been identified in the latter, no mechanisms for epididymal immunotolerance have been identified to date. Therefore, data are currently insufficient to explain how the immune system tolerates the extremely large load of novel antigens expressed on sperm, which become present in the male body after puberty, i.e., long after central tolerance was established. This study tested the hypothesis that transforming growth factor beta (TGF beta) signaling in dendritic cells (DCs) is required for immunotolerance to sperm located in the epididymis, and that male mice lacking TGF beta signaling in DCs would develop severe epididymal inflammation. To test this, we employed adult Tgfbr2(Delta DC) males, which exhibit a significant reduction of Tgfbr2 expression and TGF beta signaling in DCs, as reported previously. Results show that Tgfbr2(Delta DC) males exhibit sperm-specific immune response and severe epididymal leukocytosis. This phenotype is consistent with epididymal loss of immunotolerance to sperm and suggests that TGF beta signaling in DCs is a factor required for a non-inflammatory steady state in the epididymis, and therefore for male tract homeostasis and function.

VANDELS is a uniquely deep spectroscopic survey of high-redshift galaxies with the VIMOS spectrograph on ESO's Very Large Telescope (VLT). The survey has obtained ultradeep optical (0.48 < lambda < 1.0 mu m) spectroscopy of similar or equal to 2100 galaxies within the redshilt interval 1.0 <= z <= 7.0, over a total area of similar or equal to 0.2 deg(2) centred on the CANDLES Ultra Deep Survey and Chandra Deep Field South fields. Based on accurate photometric redshift. pre-selection, 85 per cent of the galaxies targeted by VANDELS were selected to be at z >= 3. Exploiting the red sensitivity of the refurbished VIMOS spectrograph, the fundamental aim of the survey is to provide the high-signal-to-noise ratio spectra necessary to measure key physical properties such as stellar population ages, masses, metallicities, and outflow velocities from detailed absorption-line studies. Using integration times calculated to produce an approximately constant signal-to-noise ratio (20 < t(int) < 80 h), the VANDELS survey targeted: (a) bright star-forming galaxies at 2.4 <= z <= 5.5, (b) massive quiescent galaxies at 1.0 <= z <= 2.5, (c) fainter star-forming galaxies at 3.0 <= z <= 7.0, and (d) X-ray/Spitzer-selected active galactic nuclei and Herschel-detected galaxies. By targeting two extragalactic survey fields with superb multiwavelength imaging data, VANDELS will produce a unique legacy data set for exploring the physics underpinning high-redshift. galaxy evolution. In this paper, we provide an overview of the VANDFTS survey designed to support the science exploitation of the first ESO public data release, focusing on the scientific motivation, survey design, and target selection.

This paper describes the second data release (DR2) of the Beijing-Arizona Sky Survey (BASS). BASS is an imaging survey covering a 5400 deg(2) footprint in the g and r bands using the 2.3 m Bok telescope. DR2 includes the observations through 2017 July obtained by BASS and by the Mayall z-band Legacy Survey (MzLS), which used the 4 m Mayall telescope to observe the same footprint. BASS and MzLS have completed 72% and 76% of their observations. The two surveys will be served for the spectroscopic targeting of the upcoming Dark Energy Spectroscopic Instrument. Both BASS and MzLS data are reduced by the same pipeline. We have updated the basic data reduction and photometric calibrations in DR2. In particular, source detections are performed on stacked images, and photometric measurements are co-added from single-epoch images based on these sources. The median 5 sigma point-source depths after Galactic extinction corrections are 24.05, 23.61, and 23.10 mag for the g, r, and z bands, respectively. The DR2 data products include stacked images, co-added catalogs, and single-epoch images and catalogs. The BASS website (http://batc.bao.ac.cn/BASS/) provides detailed information and links to download the data.

We introduce a new method for determining the influence of galaxies and active galactic nuclei (AGN) on the intergalactic medium (IGM) at high redshift and illustrate its potential via a first application to the field of the z = 6.42 QSO J1148+5251. Correlating spatial positions Lyman break galaxies (LBGs) with the Lyman alpha forest seen in the spectrum of a background QSO, we provide a statistical measure of the typical escape fraction of Lyman continuum photons. Using Keck DEIMOS spectroscopy to locate seven colour-selected LBGs in the range 5,3 less than or similar to z less than or similar to 6.4 we examine the spatial correlation between this sample and Ly alpha/Ly beta transmission fluctuations in a Keck ESI spectrum of the QSO. Interpreting the statistical II I proximity effect as arising from faint galaxies clustered around the LBGs, we translate the observed mean Lyra, transmitted flux into a constraint on the mean escape fraction < f(esc)> >= 0.08 at z similar or equal to 6. We also report individual transverse II I proximity effect for a z = 6.177 luminous LBG via a Ly beta transmission spike and two broad Ly alpha transmission spikes around the z = 5.701 AGN. We discuss the origin of such associations which suggest that while faint galaxies are primarily driving reionization, luminous galaxies and AGN may provide important contributions to the UV background or thermal fluctuations of the IGM at z similar or equal to 6. Although a limited sample, our results demonstrate the potential of making progress using this method in resolving one of the most challenging aspects of the contribution of galaxies and AGN to cosmic reionization.

The impact of changes in incoming solar irradiance on stratospheric ozone abundances should be included in climate simulations to aid in capturing the atmospheric response to solar cycle variability. This study presents the first systematic comparison of the representation of the 11-year solar cycle ozone response (SOR) in chemistry-climate models (CCMs) and in pre-calculated ozone databases specified in climate models that do not include chemistry, with a special focus on comparing the recommended protocols for the Coupled Model Intercomparison Project Phase 5 and Phase 6 (CMIP5 and CMIP6). We analyse the SOR in eight CCMs from the Chemistry-Climate Model Initiative (CCMI-1) and compare these with results from three ozone databases for climate models: the Bodeker Scientific ozone database, the SPARC/Atmospheric Chemistry and Climate (AC&C) ozone database for CMIP5 and the SPARC/CCMI ozone database for CMIP6. The peak amplitude of the annual mean SOR in the tropical upper stratosphere (1-5 hPa) decreases by more than a factor of 2, from around 5 to 2 %, between the CMIP5 and CMIP6 ozone databases. This substantial decrease can be traced to the CMIP5 ozone database being constructed from a regression model fit to satellite and ozonesonde measurements, while the CMIP6 database is constructed from CCM simulations. The SOR in the CMIP6 ozone database therefore implicitly resembles the SOR in the CCMI-1 models. The structure in latitude of the SOR in the CMIP6 ozone database and CCMI-1 models is considerably smoother than in the CMIP5 database, which shows unrealistic sharp gradients in the SOR across the middle latitudes owing to the paucity of long-term ozone measurements in polar regions. The SORs in the CMIP6 ozone database and the CCMI-1 models show a seasonal dependence with enhanced meridional gradients at mid-to high latitudes in the winter hemisphere. The CMIP5 ozone database does not account for seasonal variations in the SOR, which is unrealistic. Sensitivity experiments with a global atmospheric model without chemistry (ECHAM6.3) are performed to assess the atmospheric impacts of changes in the representation of the SOR and solar spectral irradiance (SSI) forcing between CMIP5 and CMIP6. The larger amplitude of the SOR in the CMIP5 ozone database compared to CMIP6 causes a likely overestimation of the modelled tropical stratospheric temperature response between 11-year solar cycle minimum and maximum by up to 0.55 K, or around 80% of the total amplitude. This effect is substantially larger than the change in temperature response due to differences in SSI forcing between CMIP5 and CMIP6. The results emphasize the importance of adequately representing the SOR in global models to capture the impact of the 11-year solar cycle on the atmosphere. Since a number of limitations in the representation of the SOR in the CMIP5 ozone database have been identified, we recommend that CMIP6 models without chemistry use the CMIP6 ozone database and the CMIP6 SSI dataset to better capture the climate impacts of solar variability. The SOR coefficients from the CMIP6 ozone database are published with this paper.

We present the North Galactic Cap sample of the Extremely Luminous Quasar Survey (ELQS-N), which targets quasars with M-1450 < -27 at 2.8 <= z < 5 in an area of similar to 7600 deg(2) of the Sloan Digital Sky Survey (SDSS) footprint with 90 degrees < R.A. < 270 degrees. Based on a near-infrared/infrared JKW2 color cut, the ELQS selection efficiently uses random forest methods to classify quasars and to estimate photometric redshifts; this scheme overcomes some of the difficulties of pure optical quasar selection at z approximate to 3. As a result, we retain a completeness of > 70% over z similar to 3.0-5.0 at m(i) less than or similar to 17.5, limited toward fainter magnitudes by the depth of the Two Micron All Sky Survey. The presented quasar catalog consists of a total of 270 objects, of which 39 are newly identified in this work with spectroscopy obtained at the Vatican Advanced Technology Telescope and the MMT 6.5 m telescope. In addition to the high completeness, which allowed us to discover new quasars in the already well-surveyed SDSS North Galactic Cap, the efficiency of our selection is relatively high at similar to 79%. Using 120 objects of this quasar sample we are able to extend the previously measured optical quasar luminosity function (QLF) by one magnitude toward the bright end at 2.8 <= z <= 4.5. A first analysis of the QLF suggests a relatively steep bright-end slope of beta approximate to -4 for this sample. This result contrasts with previous results in the same redshift range, which find a much flatter slope around beta similar to -2.5, but agrees with recent measurements of the bright-end slope at lower and higher redshifts. Our results constrain the bright-end slope at z = 2.8-4.5 to beta < -2.94 with a 99% confidence.

Humoral immunity involves multiple checkpoints that occur in B cell development, maturation, and activation. The pre-B-cell receptor (pre-BCR) is expressed following the productive recombination of the immunoglobulin heavy-chain gene, and sSignalsing through the pre-BCR are required for the differentiation of pre-B cells into immature B cells. However, the molecular mechanisms controlling the pre-BCR expression and signaling strength remain undefined. Herein, we probed the role of the endoplasmic reticulum-associated, stress-activated E3 ubiquitin ligase HMG-CoA reductase degradation 1 (Hrd1) in B cell differentiation. Using mice with a specific Hrd1 deletion in pro-B cells and subsequent B cell developmental stages, we showed that the E3 ubiquitin ligase Hrd1 governs a critical checkpoint during B cell development. We observed that Hrd1 is required for degradation of the pre-BCR complex during the early stage of B cell development. As a consequence, loss of Hrd1 in the B cell lineage resulted in increased pre-BCR expression levels and a developmental defect in the transition from large to small pre-B cells. This defect, in turn, resulted in reduced fewer mature B cells in bone marrow and peripheral lymphoid organs. Our results revealed a novel critical role of Hrd1 in controlling a critical checkpoint in B cell-mediated immunity and suggest that Hrd1 may functioning as an E3 ubiquitin ligase of the pre-BCR complex.

Observational tests of the white dwarf mass-radius relationship have always been limited by the uncertainty in the available distance measurements. Most studies have focused on Balmer line spectroscopy because these spectra can be obtained from ground-based observatories, while the Lyman lines are only accessible to space-based UV telescopes. We present results using parallax data from Gaia DR2 combined with space-based spectroscopy from HST and FUSE covering the Balmer and Lyman lines. We find that our sample supports the theoretical relation, although there is at least one star which is shown to be inconsistent. Comparison of results between Balmer and Lyman line spectra shows they are in agreement when the latest broadening tables are used. We also assess the factors which contribute to the error in the mass-radius calculations and confirm the findings of other studies which show that the spread in results for targets where multiple spectra are available is larger than the statistical error. The uncertainty in the spectroscopically derived log g parameter is now the main source of error rather than the parallax. Finally, we present new results for the radius and spectroscopic mass of Sirius B which agree with the dynamical mass and mass-radius relation within 1 sigma.

Magnetization switching utilizing the spm-orbit torque of heavy metals is a promising alternative to spin-transfer torque for a faster and more energy-efficient write mechanism for magnetic random-access memory. We report spm-orbit-torque switching m 20-nm-diameter Co20Fe60B20-MgO-based perpendicular magnetic tunnel junctions with a thermal stability factor of similar to 47. Conductive atomic force microscopy was used to measure the tunnel magnetoresistance before and after current pulses through the heavy metal underlayer, and magnetostatic shifts m the minor loops provided evidence of spm-orbit-torque switching. Comparison of estimated critical current densities and write energies suggests that spm-orbit torque can be used as an effective switching mechanism for small and thermally stable perpendicular magnetic tunnel junctions.

Recent studies have revealed intense ultraviolet (UV) metal emission lines in a modest sample of z > 7 Lyman-alpha emitters, indicating a hard ionizing spectrum is present. If such high ionization features are shown to he common, it may indicate that extreme radiation fields play a role in regulating the visibility of Ly alpha in the reionization era. Here, we present deep near-infrared spectra of seven galaxies with Ly alpha, emission at 5.4 < z < 8.7 (including a newly confirmed lensed galaxy at z(Ly alpha) = 6.031) and three bright z similar or equal to 7 photometric targets. In nine sources, we do not detect UV metal lines. However in the z(Ly alpha) = 8.683 galaxy IEGSY8p7, we detect a 4.6 sigma emission line in the narrow spectral window expected for N v lambda 1243. The feature is unresolved (FWHM < 90 km s(-1)) and is likely nebular in origin. A deep H-band spectrum of FGSY8p7 reveals non-detections of C IV, He II, and O III], The presence of N v requires a substantial flux of photons above 77 eV, pointing to a hard ionizing spectrum powered by an active galactic nucleus or fast radiative shocks. Regardless of its origin, the intense radiation field of EGSY8p7 may aid the transmission of Ly alpha through what is likely a partially neutral intergalactic medium. With this new detection, live of 13 known Ly alpha emitters at z > 7 have now been shown to have intense UV line emission, suggesting that extreme radiation fields are commonplace among the Ly alpha population. Future observations with JWST will eventually clarify the origin of these features and explain their role in the visibility of Ly alpha, in the reionization era.

Stellar tidal streams provide an opportunity to study the motion and structure of the disrupting galaxy as well as the gravitational potential of its host. Streams around the Milky Way are especially promising as phase space positions of individual stars will he measured by ongoing or upcoming surveys. Nevertheless, it remains a challenge to accurately assess distances to stars farther than 10 kpc from the Sun, where we have the poorest knowledge of the Galaxy's mass distribution. To address this, we present observations of 32 candidate RR Lyrae stars in the Orphan tidal stream taken as part of the Spitzer Merger History and Shape of the Galactic Halo (SMHASH) program. The extremely tight correlation between the periods, luminosities, and metallicities of RR Lyrae variable stars in the Spitzer IRAC 3.6 mu m band allows the determination of precise distances to individual stars; the median statistical relative distance uncertainty to each RR Lyrae star is 2.5 per cent. By fitting orbits in an example potential, we obtain an upper limit on the mass of the Milky Way interior to 60 kpc of 5.6(-1.1)(+1.2) x 10(11) M-circle dot, bringing estimates based on the Orphan Stream in line with those using other tracers. The SMHASH data also resolve the stream in line-of-sight depth, allowing a new perspective on the internal structure of the disrupted dwarf galaxy. Comparing with N body models, we find that the progenitor had an initial dark halo mass of approximately 3,2 x 10(9) M-circle dot, placing the Orphan Stream's progenitor amongst the classical dwarf spheroidals.

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